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Genome Med., Aug 06 2025, 17 (1) | https://doi.org/10.1186/s13073-025-01513-w Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders

Jihoon G. Yoon ^1,2†, Hyunsoo Jang ^3,4†, Seungbok Lee^1,5, Se Song Jang ⁵, Soojin Park ⁵, Jaeso Cho^1,5,6, Minji Kim^3,4, Jiye Han ^3,4, Hyounji Yun ^3,4, Man Jin Kim ¹, Soo Yeon Kim ^1,5, Woo Joong Kim⁵, Anna Cho ⁶, Jin Sook Lee ⁷, Murim Choi ⁸, Alberto Fernandez-Jaen ⁹, Sebastian Silva ^10,11, Reinaldo Uribe-San-Martín ^12,13, Christian Cantillano^13,14, Noriko Miyake ¹⁵, Byung Chan Lim ⁵, Jung Min Ko ⁵, Ki Joong Kim ⁵, Ki-Jun Yoon^3* and Jong-Hee Chae ^1,5*

¹Department of Genomic Medicine, Rare Disease Center, Seoul National University Children’s Hospital and Seoul National University College of Medicine, Daehak-Ro 101, Jongno-Gu, Seoul 03080, Republic of Korea.
²Department of Laboratory Medicine, Gangnam Severance Hospital and Yonsei University College of Medicine, Seoul, Republic of Korea.
³Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
⁴KAIST Stem Cell Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁵Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea.
⁶Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
⁷Department of Pediatrics, Seoul National University Hospital Child Cancer and Rare Disease Administration, Seoul National University Children’s Hospital, Seoul, Republic of Korea.
⁸Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁹Department of Pediatric Neurology, Neurogenetic Section, Hospital Universitario Quironsalud, Universidad Europea, Madrid, Spain.
¹⁰Child Neurology Service, Hospital de Puerto Montt, Puerto Montt, Chile.
¹¹Escuela de Medicina, Universidad San Sebastián, Sede Patagonia, Puerto Montt, Chile.
¹²Departamento de Neurología, Pontifcia Universidad Católica de Chile, Santiago, Chile.
¹³National Reference Center for Epilepsy, Hospital Dr. Sótero del Río, Santiago, Chile.
¹⁴Neurosurgery Department, Pontifcia Universidad Católica de Chile, Santiago, Chile.
¹⁵Department of Human Genetics, National Institute of Global Health and Medicine, Japan Institute for Health Security, Tokyo, Japan.

^†These authors contributed equally

^*Corresponding authors: correspondence to Ki-Jun Yoon or Jong-Hee Chae

Abstract

Background
Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood.

Methods
We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models.

Results
Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development.

Conclusions
This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.

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